Global Guidelines for the Care
of Patients with Hereditary
Angioedema
World Allergy Organization
General Advisors
WAO President Ruby Pawankar, Professor, Nippon Medical School, Tokyo
WAO Past President (Initiator of the guideline development)
Richard Lockey, Professor of Medicine, University of South Florida
Steering Committee Chair:
Timothy Craig, Professor of Medicine and Pediatrics, Penn State University
Members of the Steering committee:
Emel Aygoren-Pursun, Professor of Medicine, University of Frankfurt
Konrad Bork, Professor of Medicine, Johannes Gutenberg University Mainz
Tom Bowen, Professor of Medicine, Universiy of Calgary
Henrik Boysen, Executive Director, HAEi-International Patient Organization
Marco Cicardi, Professor of Medicine, University of Milan
Henriette Farkas, Professor of Medicine, Semmelweis University
Anete Grumach, Faculty of Medicine, University of Sao Paulo
Connie Katelaris, Professor of Medicine, Allergy University of Western Syndney
Hilary Longhurst, Consultant Immunologist, Barts and the London NHS Trust
William R. Lumry, Professor of Medicine, University of Texas Southwestern
Inmaculada Martinez-Saguer, Professor of Medicine, University of Frankfurt
Marcus Maurer, Professor of Dermatology and Allergy, Charité - Universitätsmedizin Berlin
Bruce Ritchie, Professor of Medicine, University of Alberta
Bruce Zuraw, Professor of Medicine, University of California San Diego
Pharmaceutical Supporters of the Guidelines in
Alphabetical Order
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CSL Behring
Dyax
Shire
Viropharma
World Allergy Organization’s HAE Global
Guidelines
• Objective: To develop a global approach for the management of
patients with Hereditary Angioedema (HAE) so as to improve the
quality of care delivered to patients with HAE globally, to increase
the availability of HAE medications globally, and to encourage all
physicians, patients, pharmaceutical companies and governments
to ensure that patients with HAE are given similar access to
therapies and care in an appropriate manner worldwide.
C1-esterase Inhibitor Protein (C1INH)
• Major inhibitor of several complement proteases (C1r, C1s, and
mannose-binding lectin–associated serine protease [MASP] 1 and 2)
and contact-system proteases (plasma kallikrein and coagulation
factor XIIa) and a relatively minor inhibitor of the fibrinolytic
protease plasmin and the coagulation protease factor XIa.
• C1-INH is deficient (type 1) or abnormal in function (type 2), but
normal in type III HAE
C1-INH involved in 3 systems → C1-INH depletion
Factor XIIa
C1-INH
Factor XII
Contact System C1-INH
Prekallikrein
HMW-K
Kallikrein
Increased vascular
permeability 
ANGIOEDEMA
Complement
System
C1rs
Plasminogen
Bradykinin
C1
Plasmin
Fibrinolytic
System
C4
C2
Bradykinin is Responsible for the Angioedema
associated with HAE
• Complement and contact plasma proteolytic cascades are activated
with the potential to generate several vasoactive compounds.
• Bradykinin is generated through activation of the contact system
• Bradykinin is the primary mediator of swelling
• Plasma kallikrein and factor XII are normally inhibited by C1INH
• Plasma kallikrein cleaves high molecular weight kininogen
How Does BK Cause Angioedema?
Increased vascular permeability
VE-cadherin
Non stimulated
Stimulated
from Tiruppathi C, et al. Vascul Pharmacol. 2003;39:173-185.
Actin stress fibers
Suspect HAE when a patient presents with angioedema, especially
if free of urticaria, that is unpredictable in onset, but frequently
follows a trigger such as trauma, and is associated with recurrent
abdominal pain and upper airway swelling. (100% consensus)
Triggers for HAE
•
•
•
•
•
•
•
•
Estrogen
ACE-inhibitors
Trauma
Dental and surgical procedures
Stress
Infections
Menstruation
Pregnancy
HAE Attacks can Involve
•
•
•
•
•
Face
Extremities
Upper airways
Gastrointestinal system
Genital-urinary system
Intestinal swelling during an Abdominal
attach
Patients with suspicion of HAE and family members of
patients with HAE should be screened so that
appropriate therapy can be available for treatment,
especially since the first event may manifest in the
upper airway and potentially may be fatal without
appropriate therapy. (100% consensus)
• All patients with HAE should have an action plan.
• Patients may be asymptomatic even later in life; however,
preparation is needed to have therapy available for procedures that
can trigger HAE
• In order to be prepared, all patients with suspected HAE and all
family members of patients diagnosed with HAE should be
screened for at least C4 and if positive, they should have an action
plan and 2 doses of on demand therapy.
DIAGNOSING HAE
Clinical symptoms + Familial history
C4
Normal
Low
Confirm C4
during attack
C1INH level
Normal
Low
Normal
Functional
C1INH
Consider HAE
type III or AE due
to medications
C1q
Normal
Low
Normal
Low
Consider other
causes of C4
consumption
HAE
type II
HAE
type I
AAE
Treatment of HAE
• Acute treatment of attacks (On Demand)
• Short Term Prophylaxis (pre-procedural)
• Long Term Prophylaxis (Suppression of attacks)
On Demand Therapies
•
•
•
•
•
C1-esterase inhibitor (C1=INH)
Recombinant C1-INH (rcC1-INH)
Ecallantide
Icatibant
Fresh Frozen Plasma
Indications of C1-INH are partially off label and all
plasma derived products can be used in place of
each other (100%)
Berinert®
all types of attacks in adults, children, pregnant women also during
breastfeeding. Dose is 20units/kg
Cinryze ®
all types of attacks in adults, children, pregnant women also during
breastfeeding. Dose is 1000 units
Cetor ®
all types of attacks in adults, children, pregnant women also during
breastfeeding. Dose is 1000 units
Use of C1-INH in HAE
Recommendation:
• The risk versus benefits of C1INH favors benefits. Few adverse
events have been reported. All 3 products are equal in efficacy and
adverse effect profile; however, the need for repeat dosing is less
with the initial use of 20 units/kg. The risk is minimal, but absolute
safety cannot be assumed since it is a human blood product. (100%)
ADVANTAGES of C1-INH
• A natural product
• Inhibits all cascade systems involved in the
generation of bradykinin
• Its half-life is longer than those of other drugs for
AT; it rapidly reaches peak plasma concentration
• Rapid onset of action
• Lack of rebound angioedema
• Effective in all types of attacks
• Appears to be safe for children
• Appears to be safe for pregnant women
• Safe for home use
• Minimal allergic reaction
• No tachyphylaxis
• Long (30 years of) clinical experience
DRAWBACKS
• Expensive (but its price is not higher
than those of other drugs except
FFP)
• Potential risk for the transmission of
other diseases and infective agents
• Intravenous administration
• Frequent and repetitive use may
influence attack frequency and
severity
• Off label administration of high doses
is associated with thrombotic events
Recommendation: For on demand therapy
recombinant C1-INH appears to be equally
effective to plasma derived C1-INH
Differences between rcC1-INH and C1-INH
•
•
•
•
rcC1-INH half-life is 3 hours
Contains traces of rabbit antigen
Contraindicated in rabbit allergy
Unique polysaccharides are added to the protein during production.
Which shorten half life and may be allergenic
• No human blood-borne disease associated with it
Recommendation: The recommended rcC1-INH
dose for the routine treatment of acute attacks
is 50 U/kg body weight (100%)
•
•
•
•
•
Test for rabbit antibodies before using the rcC1-INH
Contains 2100 units per vial
concentration of 150 units/ml
treatment of acute attacks is 50 U/kg body weight
maximum of 4200 U (2 vials) for patients of or over 84kg body
weight
• second injection may be given if the patient does not improve
satisfactorily after the first dose
ADVANTAGES of rcC1-INH
• Inhibits all cascade systems involved in the
generation of bradykinin
• Rapid onset of action
• Lack of rebound angioedema
• Effective in all types of attacks
• Safe for children
• Safe for pregnant women
• Minimal allergic reaction
• No tachyphylaxis
• No viral transmission
• Unlimited supply
DRAWBACKS
• Expensive (but its price is not higher
than those of other drugs except
FFP)
• Potential risk for anaphylaxis
• Intravenous administration
• Potential, but not described, for
neutralizing antibodies and IgE to
polysaccharide added to the protein
Treatment of HAE: Icatibant
• Recommendation: Icatibant is effective for the treatment of
HAE attacks at all locations with a dose of 30 mg SQ (100%)
• Recommendation: Repeat dosing of icatibant is necessary in
up to 10% of attacks and 1% require a third dose to treat an
HAE attack. (not voted)
Positives
• Ease of Use
• Rapid to Administer
• Appear to have good safety profile
•Not blood product
•Not immunogenic
• Alternative to C1 inhibitor
• Ideal for self administration
• May address problem of delays in
accessing treatment
• Not Intravenous
Negatives
• Short half life-probably not
suitable for prophylaxis
• Need for repeat dosing
• Not currently
recommended for
pregnant women or
children
• No action on other
systems regulated by C1
inhibitor
• Pain and burning at
injection site
Cicardi et al NEJM 2010
Treatment of HAE: Ecallantide
• Recommendation: Ecallantide at 30 mg SQ can be used to
treat HAE attacks at all locations (100%)
• Recommendation: Self injection of ecallantide should be
avoided secondary to a small, but real risk of anaphylaxis
(100%)
Treatment of HAE: Ecallantide
• Allergic reactions occur in approximately 3% of patients that receive
ecallantide.
• IgG and IgE antibodies are produced against ecallantide, but the IgG
does not appear to be neutralizing.
• Approved in the USA to be giving at home by a health care provider
equipped and trained to treat anaphylaxis
Recommendation: Fresh Frozen Plasma should only be
used for on-demand therapy when other medications are
not available (100%)
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•
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action- replaces C1-INH
indication- not indicated unless no other treatments are available
method- 2 units for adults, weight based for children
adverse events – anaphylaxis, worsening of HAE, viral transmission
positives and negatives- negatives out-weigh positives and FFP
should be avoided if other therapies are available
How Do the Newer Drugs Compare?
Drug
Advantages
Disadvantages
Best use
Status
Plasmaderived
C1-INH
• Extensive clinical
experience
• Corrects the
fundamental defect
• long half-life
• Infectious risk
• Needs IV access
• Limited supply
• Acute attacks
• Short-term
• Long-term
prophylaxis
• Prodromes
• Berinert P:
approved for attacks
• Cinryze: approved
for prophylaxis and
attacks
• Cetor approved for
attacks
Recombinant
C1-INH
• Corrects the
fundamental defect
• No human virus
risk
• Scalable supply
• Needs IV access
• Short half-life
• Potential for
allergic reactions
• Acute attacks
• Short
prophylaxis
• Prodrome?
• Rhucin: used for
attacks
Ecallantide
• More potent than
C1-INH
• No infectious risk
• Subcutaneous
administration
• Antibodies may
cause allergic
reaction or
neutralization
• Short half-life
• Acute attacks
in office or by
HCP in home
• Kalbitor approved
for administration
by HCP for
attacks
Icatibant
• No infectious
risk
• Stable at room
temperature
• Subcutaneous
• Short half-life
• Local pain or
irritation
• Home
treatment of
acute attacks
• Firazyr: used for
attacks
Short-term or pre-procedural therapy: Indication
• Prior to some surgeries; especially
– dental/ intraoral surgery
– where intubation is required
– major surgery
• To cover periods of high risk for attacks
– increased likelihood of attack
– increased consequence of attack
Evidence limited to case reports/ small series –
recommendation based on expert opinion
Short term prophylaxis for lower risk
procedures
• For lower risk procedures, or where safe prophylactic agents are
not available, prophylaxis may be omitted
• the patient should be aware of the risk of and have a management
plan for attacks, which are more likely to occur after surgery.
– Two doses of C1 inhibitor, ecallantide or icatibant should be
immediately available.
• [100% agreement. Observational/ case series]
Short-term or pre-procedural therapy:
Attenuated Androgens - REGIMEN
Document
Recommendation
Alternative
Children
Duration
UK
Consensus
2005
Danazol 200600 mg
Stanozolol 2-6
mg od
Danazol
300mg od
5 days before,
2 days after
procedure
International
(Canadian/
Hungarian)
Consensus
2010
Danazol 2.510mg/kg//day:
max 600 mg /
Stanozolol 4-6
mg od
Farkas 2010
Danazol
600mg
Doses are based on expert opinion: not evidence-based
5 days before,
2 days after
procedure
4 days before
and after
procedure
Androgens as short term prophylaxis
Advantages
Disadvantages
Ease of use
Perceived inferior efficacy to C1 inhibitor
Well tolerated in short term
(usually)
Need to start several days prior to procedure
Concern of side effects, but minimal
Have been used in children
without problem
Not suitable for most children
Have been used in pregnancy (3rd
trimester) without problem
Not suitable for most pregnant women and
during breast feeding
Low cost
Unavailable in some countries
Broad availability
Advantages and disadvantages for C1-inhibitor
for short term prophylaxis
Advantages
Disadvantages
Some evidence for efficacy
Good theoretical rationale for use
Intravenous
Well tolerated
Lack of availability in some countries
Treatment of choice in children and
pregnancy
Cost
May give additional doses if swellings
occur
Therapies not to be used for short term
prophylaxis
• The following are not recommended:
– Plasma (FFP/SDP)*. (only if no other therapies are
available)
– Icatibant
– Ecallantide
– Methyl testosterone
• Probably effective.
– Ruconest/ Rhucin
• [100% agreement except for plasma (75% agreement). Expert
opinion]
• Recommendation: Chronic Prophylaxis is indicated when
on demand therapy fails to improve the quality of life of a
patient with HAE (100%)
Chronic Prophylaxis: Anti-fibrinolytics
• Recommendation: Anti-fibrinolytics are have little benefit,
have adverse events and are not indicated for use in
prophylaxis of HAE (65%)
• Recommendation: The minority recommended use in prepuberty children for HAE prophylaxis (35%)
• Recommendation: Avoid use of anti-fibrinolytics during
pregnancy and lactation (80%)
Anti-fibrinolytic use for chronic prophylaxis
advantages
disadvantages
• Inexpensive
• Availability
• Adverse effects
• Few data to support
effectiveness
• Multiple daily dosing
• Unsure of status during
pregnancy, lactation and
pre-puberty
Chronic Prophylaxis: Androgens
• Recommendation: Androgens are effective to control the
symptoms of HAE, but secondary to the potential adverse
effects the dose should not exceed Danazol 200 mg a day or
an equivalent dose of an alternate androgen and the dose
should be reduced to the least effective dose (100%)
• Recommendation: Androgens should be avoided during
pregnancy, lactation and in most children before puberty
(100%)
Monitoring for adverse events when using
androgens for Chronic Prophylaxis (100%)
Before use and every 6 months:
• Fasting lipid profile
• Liver function studies and biochemistry
• Complete blood cell count
• Urinalysis
• Alfa-fetal protein
Before use and every 12 months:
• abdominal liver ultrasonography
8.5 Monitoring while receiving
treatment with Androgens
Before
Follow up
Liver Functional Tests
Every 6 months
Lipid profile
Every 6 months
Urine analysis
Every 6 months
Abdominal ultrasound
Once/year
Alpha fetoprotein
Every 6 months
CBC
Every 6 months
Use of C1-INH for chronic prophylaxis
• Recommendation: C1-INH that is human plasma derived can
be used at 1000 units IV twice a week to suppress HAE attacks.
Doses as low as 500 units may be effective in some and others may
require greater than 1000 units. (100%- rating A)
• Recommendation: Human derived C1-INH products should be
equally effective, but the shorter half-life of recombinant C1-INH
may limit its use for chronic prophylaxis (90%)
Dosing C1-INH for Chronic Prophylaxis
• The approved dose is 1000 units twice a week.
• At this dose breakthrough attacks are not infrequent
• Higher doses and more frequent dosing may be necessary to
prevent breakthrough attacks.
• Optimal dosing of C1-INH for chronic use has not yet be determined
Use of C1-INH for Chronic Prophylaxis
• Recommendation: Before starting C1-INH hepatitis B, C, HIV and
parvovirus titers should be obtained and monitored on a yearly
basis (100%)
• Recommendation: Upon prescribing C1-INH hepatitis B and A
vaccine series should be started (no vote)
• Recommendation: Because of the risk of thrombosis with central
lines indwelling central lines and catheters should be avoided when
administered C1-INH for chronic prophylaxis (100%)
Use of C1-INH for Chronic Prophylaxis
Advantages
Disadvantages
• Effective
• Few adverse events
• Long safety record from over 3
decades use in the EU
• Dose ranging studies are
lacking
• Human plasma derived
• Breakthrough attacks occur
despite 1000 units twice a
week
• Intravenous dosing necessary
• Expensive
Preventive and long term care of the patient
with HAE
• Recommendation: All patients with HAE should have at least an
annual assessment by an HAE specialist. (100%)
• Recommendation: All patients with HAE should have an action
plan and product available to treat an attack of HAE. (100%)
Preventive and long term care of the patient
with HAE
• All HAE patients have a potential for receiving human blood
products. Because of this all HAE patients should be screened as
early as possible for Hepatitis B and C and HIV. In addition,
vaccination for Hepatitis B and possibly A should be stressed.
Annual assessment for infections with hepatitis and HIV are
suggested. (100%)
Drugs to avoid in HAE
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•
•
•
Estrogen birth control
Estrogen hormone replacement
ACE-inhibitors for blood pressure, CHF and other diseases
Agreement: 100%
8.8 screening summary
Tests
Androgens
Plasmin
inhibitors
Liver Functional Tests
Q 6 mth
Q 6 mth
Lipid profile
Q 6 mth
Renal function
Q 6 mth
Urine analysis
Q 6 mth
Abdominal ultrasound
Q 12 mth
Alpha fetoprotein
Q 6 mth
Q 6 mth
CPK
Q 6 mth
Eye pressure
Q 6 mth
Thrombophilia tests?
At start of
therapy
Serology for HIV,
hepatitis B, C, E,
Parvovirus
Plasma
derived
C1INH/
Plasma
Start of therapy
and every year
Why Children with HAE are Unique

Teachers and health care personnel responsible for the child at
school should be informed in writing of the diagnosis.

Special medication and an action plan for emergency treatment
should be made available at home, at school, and field trips.

A proportion of attacks can be prevented through appropriate
counseling and lifestyle modifications aimed at eliminating
triggering factors.

Stigmatization by peers is more frequent in children, than in adults.
Treating attacks of HAE
•
C1-INH concentrate is effective and safe.
•
Probably the best dose should be based on 20 units/kg since other
weight based dosing is not available
•
No experience is as yet available with the pediatric use of the
innovative drugs (bradykinin receptor B2 antagonist, kallikrein
inhibitor, recombinant C1-INH concentrate).
Treatment of Children with HAE
Drugs and the indications for their use are the same as in adults.
Short-Term Prophylaxis (STP)
•
•
•
Short term use of androgens is tolerated well.
Preferred pre-procedural treatment is with C1-inhibitor.
FFP can be utilized, but only in cases C1-inhibitor is not available.
Chronic Prophylaxis
• In severe cases uncontrolled by on demand therapy of acute attacks chronic
prophylaxis may be necessary
• C1-inhibitor prophylaxis is preferred in children
• Androgens can be used, but toxicity often exceeds benefits and should be
reserved only in severe uncontrolled cases where other therapies are not
available.
• Anti-fibrinolytics have minimal efficacy, but may be tried in children
Treatment during Gestation and Lactation
• Recommendation: Because of the lack of safety data with
icatibant and ecallantide and the toxicity of androgens and
antifibrinolytics during pregnancy, C1INH is the preferred drug
during pregnancy and lactation.
• (100% expert opinion)
On-Demand Therapy during Gestation and
Lactation
• C1-inhibitor is the preferred therapy. Presently, until further
information is available the dose would be 20 units/kg (majority).
Minority opinion is 500 or 1000 units for an attack (minority
opinion)
• FFP (heat treated) can be substituted if C1-inhibitor is not available,
but risk is greater than with C1-inhibitor
• Anti-fibrinolytics should be avoided
• No data are available for eccalantide or icatibant and both should
be avoided until safety data exists
Prophylaxis During Gestation and Lactation
Elimination of Triggering Factors
The measures for non-pregnant females apply.
Drug Prophylaxis
Chronic prophylaxis:
•
•
•
•
Pd C1-INH concentrate is thought to be safe and effective during both pregnancy
and lactation.
Anti-fibrinolytics are not recommended to use during pregnancy. AFs cross the
placenta. They are not teratogenic in animals, but are excreted into breast milk.
These drugs are not recommended during breastfeeding.
Androgens are not recommended, as these drugs cross the placenta. They cause
masculinization of the female fetus, placental insufficiency, and fetal growth
retardation. No mutagenicity has been shown in animal models. Excretion into
breast milk is unknown, but androgens should be avoided during lactation.
Heat-treated fresh frozen plasma (FFP): Only limited data exist on the use of FFP
during pregnancy. Use only if no C1-inhibitor is available
Home Therapy
• Recommendation: Patients with HAE should be
encouraged to provide self care and home care to allow early,
effective and cost effective care
• Agreement: 100%
• A evidence
Action Plans
• Recommendation: All patients with HAE should have an acute
action plan to include location to acquire care, therapies available
or in possession, dose and route of administration
• Agreement: 100%
World Wide Access to Therapies
• Recommendation: Associations, doctors, patients, health care
providers, and pharmaceutical companies should petition to have
therapies available world wide for all patients with HAE.
• Agreement: 100%
Summary
• This short slide set and the document and comprehensive slide set
that accompanies it are intended for the better dissemination of
the care and treatment of patients with HAE. These slides are
available on the WAO website to be used for self learning, patient
care and teaching. Feel free to use them.